Contact-dependent growth inhibition toxins exploit multiple independent cell-entry pathways

Julia L.E. Willett, Grant C. Gucinski, Jackson P. Fatherree, David A. Low, Christopher S. Hayes

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Contact-dependent growth inhibition (CDI) systems function to deliver toxins into neighboring bacterial cells. CDI+ bacteria export filamentous CdiA effector proteins, which extend from the inhibitorcell surface to interact with receptors on neighboring target bacteria. Upon binding its receptor, CdiA delivers a toxin derived from its C-terminal region. CdiA C-terminal (CdiA-CT) sequences are highly variable between bacteria, reflecting the multitude of CDI toxin activities. Here, we show that several CdiA-CT regions are composed of two domains, each with a distinct function during CDI. The C-terminal domain typically possesses toxic nuclease activity, whereas the N-terminal domain appears to control toxin transport into target bacteria. Using genetic approaches, we identified ptsG, metI, rbsC, gltK/gltJ, yciB, and ftsH mutations that confer resistance to specific CdiA-CTs. The resistance mutations all disrupt expression of inner-membrane proteins, suggesting that these proteins are exploited for toxin entry into target cells. Moreover, each mutation only protects against inhibition by a subset of CdiA-CTs that share similar N-terminal domains. We propose that, following delivery of CdiA-CTs into the periplasm, the N-terminal domains bind specific inner-membrane receptors for subsequent translocation into the cytoplasm. In accord with this model, we find that CDI nuclease domains are modular payloads that can be redirected through different import pathways when fused to heterologous N-terminal "translocation domains." These results highlight the plasticity of CDI toxin delivery and suggest that the underlying translocation mechanisms could be harnessed to deliver other antimicrobial agents into Gram-negative bacteria.

Original languageEnglish (US)
Pages (from-to)11341-11346
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number36
DOIs
StatePublished - Sep 8 2015

Keywords

  • Bacterial cell envelope
  • Dnase activity
  • Genetic selection
  • Toxin/immunity genes
  • Trnase activity

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